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Recent randomized controlled trials (RCTs) examined the role of adding androgen receptor signaling inhibitors (ARSIs), including abiraterone acetate (ABI), apalutamide, darolutamide (DAR), and enzalutamide (ENZ), to docetaxel (DOC) and androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC).To analyze the oncologic benefit of triplet combination therapies using ARSI + DOC + ADT, and comparing them with available treatment regimens in patients with mHSPC.Three databases and meetings abstracts were queried in April 2022 for RCTs analyzing patients treated with first-line combination systemic therapy for mHSPC. The primary interests of measure were overall survival (OS) and progression-free survival (PFS). Subgroup analyses were conducted to assess the differential outcomes in patients with low- and high-volume disease as well as de novo and metachronous metastasis.Overall, 11 RCTs were included for meta-analyses and network meta-analyses (NMAs). We found that the triplet combinations outperformed DOC + ADT in terms of OS (pooled hazard ratio [HR]: 0.74, 95% confidence interval [CI]: 0.65-0.84) and PFS (pooled HR: 0.49, 95% CI: 0.42-0.58). There was no statistically significant difference between patients with low- and high-volume disease in terms of an OS benefit from adding an ARSI to DOC +ADT (both HR: 0.79; p = 1). Based on NMAs, triplet therapy also outperformed ARSI + ADT in terms of OS (DAR + DOC + ADT: pooled HR: 0.74, 95% CI: 0.55-0.99) and PFS (ABI + DOC + ADT: HR: 0.68, 95% CI: 0.51-0.91, and ENZ + DOC + ADT: HR: 0.70, 95% CI: 0.53-0.93). An analysis of treatment ranking among de novo mHSPC patients showed that triplet therapy had the highest likelihood of improved OS in patients with high-volume disease; however, doublet therapy using ARSI + ADT had the highest likelihood of improved OS in patients with low-volume disease.We found that the triplet combination therapy improves survival endpoints in mHSPC patients compared with currently available doublet treatment regimens. Our findings need to be confirmed in further head-to-head trials with longer follow-up and among various patient populations.Our study suggests that triplet therapy with androgen receptor signaling inhibitor, docetaxel, androgen deprivation therapy prolongs survival in patients with metastatic hormone-sensitive prostate cancer compared with the current standard doublet therapy.

Background Evidence suggests proton pump inhibitor (PPI) use may attenuate the effect of abiraterone acetate plus prednisone (AAP) in metastatic prostate cancer via the modification of gut microbiota. This study aimed to examine whether concomitant PPI use is associated with survival in patients with metastatic prostate cancer treated with androgen deprivation therapy (ADT) and AAP. Methods Post-hoc analysis was conducted in patients with metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC) treated in the LATITUDE, COU-AA-301, and COU-AA-302 trials (ADT vs. ADT plus AAP). PPI users and non-users were compared for restricted mean overall survival time (RMOST) and restricted mean progression-free survival time (RMPFST) based on inverse probability of treatment weight (IPTW)-adjusted Kaplan-Meier curves. IPTW-adjusted Cox regression models were used to assess heterogeneity of treatment effect. Results In patients treated with AAP, PPI use was associated with inferior RMOST [difference (95% confidence interval): -4.2 (-7.0 to -1.4)] and RMPFST [-3.5 (-6.6 to -0.4)] compared with non-users. However, RMOST and RMPFST were similar between PPI users and non-users in patients treated with ADT alone [RMOST, -2.6 (-5.8 to 0.6); RMPFST, -1.7 (-4.8 to 1.4)]. Interaction term analyses did not show evidence of heterogeneity in treatment effect between AAP and ADT, despite the prominent treatment effect shown in mCSPC vs. mCRPC. Conclusions PPI use may be associated with inferior survival in patients with metastatic prostate cancer who receive ADT plus AAP. Discontinuing unnecessary PPI use might improve those outcomes.

The lung immune prognostic index (LIPI) predicts the prognosis of patients with advanced non-small-cell lung cancer and is a prognostic biomarker for renal cell carcinoma and melanoma; however, no study has evaluated its potential as a preoperative biomarker for patients with bladder cancer (BC). We investigated the LIPI as a preoperative prognostic biomarker in patients undergoing radical cystectomy. We retrospectively analyzed the clinical records of 105 patients with BC who underwent radical cystectomy from January 2013 to June 2019. The LIPI was evaluated based on the preoperatively derived neutrophil–lymphocyte ratio and the lactate dehydrogenase levels. Inverse probability of treatment weighting (IPTW)-adjusted Kaplan–Meier curves and decision curve analysis (DCA) were performed to assess the disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) rates. The patients were classified into the good, intermediate, and poor LIPI groups [71 (67.6%), 28 (26.7%), and 6 (5.7%) patients, respectively]. IPTW-adjusted Kaplan–Meier curve analyses showed that patients with intermediate to poor LIPI had worse DFS, CSS, and OS rates than those with good LIPI. The LIPI combined with pT3/4 and lymph node metastasis could better assess the prognosis of DFS at 24 months postoperatively by DCA. The preoperative LIPI can predict the prognosis of patients with BC undergoing radical cystectomy and has a better predictive ability when combined with pT3/4 and lymph node metastasis.

BACKGROUND Although prostate cancer is a very common form of malignancy in men, the clinical significance of androgen deprivation therapy (ADT) with abiraterone acetate versus the nonsteroidal antiandrogen bicalutamide has not yet been verified in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). The present study was designed to initiate this verification in real-world Japanese clinical practice. METHODS We retrospectively analyzed the records of 312 patients with high-risk mHSPC based on LATITUDE criteria and had received ADT with bicalutamide (n = 212) or abiraterone acetate (n = 100) between September 2015 and December 2020. Bicalutamide was given at 80 mg daily and abiraterone was given at 1000 mg daily as four 250-mg tablets plus prednisolone (5-10 mg daily). Overall survival (OS), cancer-specific survival (CSS), and time to castration-resistant prostate cancer (CRPC) were compared. The prognostic factor for time to CRPC was analyzed by Cox proportional hazard model. RESULTS Patients in the bicalutamide group were older, and more of them had poor performance status (≧2), than in the abiraterone group. Impaired liver function was noted in 2% of the bicalutamide group and 16% of the abiraterone group (p

Background Randomized trials showed the survival benefits of the combined use of androgen receptor axis-targeted agents with androgen deprivation therapy in metastatic hormone-sensitive prostate cancer (mHSPC), regardless of the risk. However, treating patients with low-risk mHSPC with such intensive treatment is still debatable. Methods This retrospective study included 155 low-risk patients among 467 mHSPC patients treated in our affiliated institutions. The association between predictive factors and treatment outcomes was estimated using the Kaplan–Meier method and log-rank test. Predictive factors for castration resistant prostate cancer (CRPC)-free survival were investigated using Cox regression analyses. Results During the median follow-up of 39 months, 38.7% of patients developed CRPC and 14.2% died. In the multivariate analyses, a presence of Gleason pattern 5 (hazard ratio [HR] 2.04), high alkaline phosphatase (HR 1.007) and high lactate dehydrogenase (HR 1.009) were significant predictive factors for shorter CRPC-free survival. Finally, 155 patients were stratified into favorable- and unfavorable-risk groups based on the numbers of the predictive factors. The overall survival (OS) in the unfavorable-risk group (total scores: 2–3) was significantly worse than that of the favorable-risk group (total score: 0–1) (P = 0.02). This prognostic model was assessed with 50 low-risk mHSPC patients from the external validation dataset and found both the time to CRPC, and the OS in the unfavorable-risk group was significantly worse than that of the favorable-risk group (P Conclusions The combination of Gleason pattern 5, high alkaline phosphatase and lactate dehydrogenase can predict those with worse OS in low-risk mHSPC patients.

To assess the real-world clinical benefit of re-challenging chemotherapy after pembrolizumab in patients with metastatic urothelial carcinoma (mUC), as there have been several reports suggesting that programmed cell death protein-1/programmed death-ligand 1inhibitors can restore platinum sensitivity.Of 236 patients treated with pembrolizumab, we excluded 45 patients who did not experience progressive disease (PD) for pembrolizumab during the follow-up and 86 patients who discontinued pembrolizumab by the diagnosis of PD followed by the best supportive care. A total of 105 patients were identified for a logistic regression propensity score model to compare the survival outcomes between patients treated with continuing pembrolizumab (80) and re-challenging chemotherapy (25) after the diagnosis of PD for pembrolizumab.A median overall survival (OS) from PD for pembrolizumab was 11 months in 105 patients. Of 25 patients treated with re-challenging chemotherapy, platinum-including chemotherapy (gemcitabine and cisplatin; gemcitabine/cisplatin/paclitaxel [GCP]; methotrexate and vinblastine and adriamycin and cisplatin; and methotrexate and carboplatin and vinblastine MCAVI) was offered in 20 patients (80%). The objective response rate (ORR) for the first-line chemotherapy in the 105 patients was 30%, with a comparable ORR in 25 patients treated with re-challenging chemotherapy of 28%. GCP as a re-challenging regimen was offered in 12 of 25 (48%) patients. The ORR for the GCP regimen was 50%. Propensity score matching was performed using putative clinical factors, from which 34 patients were identified as pair-matched groups. The OS for patients treated with re-challenging chemotherapy was significantly longer than continuing pembrolizumab (a median of 13.9 and 5.8 months, respectively: P = 0.048).Re-challenging chemotherapy including platinum agents after PD with pembrolizumab offers clinical benefits in patients with mUC.

Pembrolizumab has now become a standard of care in metastatic urothelial carcinoma (mUC), although the treatment effect of the drug substantially differs among individuals. Emerging evidence suggests that radiotherapy exerts a synergistic effect with PD-1 blockade. We sought to elucidate the survival outcomes in patients who underwent palliative radiation with the pembrolizumab treatment.We retrospectively investigated our multi-institutional dataset of 235 platinum-refractory mUC patients treated with pembrolizumab as second-line treatment, collected from January 2018 and October 2021. Propensity score matching was performed to reduce biases by potential confounding factors for overall survival (OS).With a median follow-up of 6.8 months, the median OS from the initiation of pembrolizumab was 13 months in 235 patients. Palliative radiation was performed in 71 (30.2%) patients for whom the median radiation dose and fraction were 30 Gy and 10 fractions, respectively. Irradiated sites were bone in 24 (33.8%), lymph node in 17 (23.9%), lung in 3 (4.2%), brain in 8 (11.3%), and other sites in 19 (26.8%). OS from the initiation of pembrolizumab was significantly longer in patients who underwent concurrent palliative radiation with pembrolizumab (39 patients: median OS: 21 months) than in both patients with palliative radiation before pembrolizumab (32 patients: median OS: 9 months) (p = 0.001) and those without palliative radiation throughout the follow-up (164 patients: median OS: 13 months) (p = 0.019). After the propensity-score matching by putative confounding factors, longer OS in patients treated with concurrent palliative radiation with pembrolizumab (n = 36) was still observed compared to patients without the concurrent palliative radiation (n = 36) in the pair matched cohort (median OS of 29 and 13 months, respectively, p = 0.033).Our findings suggest that the concurrent administration of palliative radiation with pembrolizumab offers a favorable effect on OS in platinum-refractory mUC patients.

To investigate differential clinical outcomes in patients treated with partial nephrectomy (PN) vs. percutaneous cryoablation (PCA) for cT1b renal tumors.We retrospectively analyzed the records of 119 patients who had undergone PN (n = 90) or PCA (n = 29) for cT1b renal tumors. Inverse probability weighting (IPW) was used for balancing patient demographics, including renal function and tumor complexity. Perioperative complications, renal function preservation rates, and oncological outcomes such as local recurrence-free, metastasis-free, cancer-specific, and overall survival were compared using IPW-adjusted restricted mean survival times (RMSTs).PCA was more likely to be selected for octogenarians (odds ratio: 11.4, 95% confidence interval [CI]: 3.33-45.1). During the median follow-up of 43 months in the PCA group and 36.5 months in the PN group, unablated local residue or local recurrence was noted in 6 patients in the PCA group and local recurrence was noted in 4 patients in the PN groups. Of the 6 patients in the PCA group, 4 underwent salvage PCA, and local control had been achieved at the last visit. In the IPW-adjusted population, PCA had significantly worse local recurrence-free survival compared with PN (IPW-adjusted RMST difference: -22.7 months, 95% CI: -45.3 to -0.4, P = 0.046). IPW-adjusted RMST for metastasis-free survival (P = 0.23), cancer-specific survival (P = 0.77), and overall survival (P = 0.11) did not differ between PCA and PN. In addition, PN was not a predictor for local control failure at the last visit (odds ratio: 0.30, 95%CI: 0.05-1.29). There were no statistically significant differences between PN and PCA in renal function preservation or overall/severe complication rates.In patients with cT1b renal tumor, although the local recurrence rate is higher for PCA than for PN, PCA provides comparable distant oncologic outcomes. PCA can be an alternative treatment option for elderly, comorbid patients, even those with cT1b renal tumors.

BACKGROUND: The impact of incidental prostate cancer (IPC) on oncological outcomes after radical cystoprostatectomy (RCP) specimens from patients with bladder cancer (BC) remains controversial. This relationship has not been well elucidated in Asian countries, where the incidence of prostate cancer has recently shown dramatic increases. OBJECTIVES: This study retrospectively compared pathological features and oncological outcomes between BC patients with and without IPC in the RCP specimens. METHODS: This study included 142 men who underwent RCP for BC. Men who were previously diagnosed with prostate cancer were excluded. Each prostate gland and seminal vesicle was processed as whole mounts and 4-mm close-step sectioning was performed. A single genitourinary pathologist diagnosed IPC. The pathological features and oncological outcomes such as overall survival (OS), bladder cancer-specific survival (BCSS), and progression-free survival (PFS) were compared between patients with IPC (IPC+group, n = 45) and without IPC (IPC- group, n = 97). P values less than 0.05 considered to indicate statistical significance for patients’ characteristics. Because of multi-primary endpoint, P values less than 0.0167 was considered statistical significance for oncological outcomes. RESULTS: We detected IPC in 45 RCP specimens (31.6%). Patients in the IPC- group were significantly younger at surgery than those in the IPC+group (P

Introduction The effect of synthetic mesh after pelvic organ prolapse surgery on the progression of bladder cancer remains unclear. Case presentation A 79-year-old woman who underwent a tension-free vaginal mesh procedure 8 years prior was diagnosed with carcinoma in situ of the bladder. Although intravesical Bacillus Calmette-Guerin therapy was started, the tumor rapidly became muscle invasive. Laparoscopic radical cystectomy was performed following radiochemotherapy; however, the tumor extended to the left internal obturator muscle along the mesh arm. Pathological findings showed desmoplastic high-grade urothelial carcinoma infiltrating around the mesh. Finally, cancer recurred rapidly in the left internal obturator muscle. Conclusion Synthetic mesh can become an abnormal anatomical pathway for tumor infiltration. Therefore, in high-risk bladder cancer patients who underwent a tension-free vaginal mesh procedure, radical cystectomy should be performed without delay before the tumor invades the perivesical tissue.

Subgroup analysis of KEYNOTE-045 suggested that cigarette smoking had a positive impact on the effectiveness of pembrolizumab in patients with advanced urothelial carcinoma (UC), whereas studies on other cancers treated with immune checkpoint inhibitors reported inconsistent results. This study aimed to examine the association between smoking-related factors and the effectiveness of pembrolizumab in patients with metastatic UC. This multicenter retrospective study was conducted using data from 95 patients with metastatic UC treated with pembrolizumab. The primary outcomes were progression and all-cause mortality. Time-to-event outcomes were compared with smoking history and lifetime smoking exposure at treatment initiation. Survival curves were compared using the log-rank test, with hazard ratios (HRs) estimated from Cox regression models. Cubic spline regression analysis was used to depict event hazards. We identified 32 (34.7%) patients with heavy smoking exposure (≥ 25 pack-years). Moreover, 19 (20.0%), 36 (37.9%), and 40 (42.1%) patients were current, former, and never smokers, respectively. Multivariable models showed that heavy smoking exposure was significantly associated with lower risk of progression (HR 0.58; 95% confidence interval (CI) 0.35–0.97; P = 0.047) and all-cause mortality (HR 0.30; 95% CI 0.11–0.82; P = 0.019). Cubic spline regression analyses revealed a dose-effect relationship. No significant association was observed between smoking history alone and effectiveness of pembrolizumab. Lifetime smoking exposure plays a significant role in the effectiveness of pembrolizumab in patients with metastatic UC.

BackgroundThe KEYNOTE-045 trial showed that pembrolizumab therapy improved the survival of patients with advanced urothelial carcinoma (UC). However, its effectiveness in trial-ineligible patients remains unclear.Materials and MethodsWe conducted a multicenter retrospective study to evaluate the effectiveness of pembrolizumab in patients with metastatic UC who were trial-ineligible. The data of 222 consecutive patients with platinum-treated metastatic UC who received pembrolizumab as second-line therapy were analyzed. Trial eligibility was assessed using the KEYNOTE-045 criteria. Inverse probability weighting (IPW) was used to balance patient characteristics. Overall survival (OS) and progression-free survival (PFS) were examined using the IPW-adjusted Kaplan-Meier method. IPW-adjusted restricted mean survival times (RMSTs) were compared between trial-ineligible and trial-eligible patients.ResultsOne hundred thirty-three patients (59.9%) were classified as trial-ineligible according to the KEYNOTE-045 criteria. Patients who did not develop progression following chemotherapy were the most common reason for trial protocol violation (N = 58 [26.1%]). The trial-ineligible patients showed similar RMST for PFS (difference: 2.4 months, 95% CI: -3.2 to 8.0, P = 0.40) and OS (difference: 1.7 months, 95% CI: -8.3 to 4.9, P = 0.60) compared with the trial-eligible patients. Furthermore, patients who were trial-ineligible because of comorbidities, poor performance status, or impaired liver or kidney function also had similar RMST for PFS and OS compared with those who were trial-eligible.ConclusionsThis study suggests that the effectiveness of pembrolizumab may be retained in trial-ineligible patients with platinum-treated metastatic UC. Expanding trial eligibility criteria for these patients may be beneficial.

OBJECTIVES To assess whether a new risk stratification system according to predictors for overall survival (OS) at the diagnosis of metastatic castration-resistant prostate cancer (mCRPC) could determine treatment outcomes and assist in treatment decision-making. PATIENTS AND METHODS Two independent clinical cohorts of patients, treated with androgen signalling inhibitors (ASIs: abiraterone and enzalutamide) or docetaxel as a first-line treatment for mCRPC, were used in this study: a derivation cohort (196 patients with mCRPC) and an external validation cohort (211 patients with mCRPC). RESULTS Three independent predictors for OS, including duration of initial androgen deprivation therapy 350 U/dL and haemoglobin level

OBJECTIVE To evaluate the clinical usefulness of Immunotherapy Response Evaluation Criteria in Solid Tumours (iRECIST) in patients with metastatic urothelial carcinoma (UC) treated with pembrolizumab. The iRECIST is designed to accurately capture the tumour response treated with immunotherapy. PATIENTS AND METHODS We conducted a multicentre retrospective study evaluating the clinical utility of iRECIST in 91 patients with metastatic UC treated with second-line pembrolizumab. The objective response (OR) and time to progression (TTP) in accordance with both iRECIST and RECIST version 1.1 were compared with overall survival (OS) and risk of all-cause mortality, and analysed using log-rank and multivariable Cox regression models, respectively. Predictive performance of the criteria was studied using Harrell's concordance index (c-index). The clinical usefulness of each criterion was compared using decision curve analysis. RESULTS Of 57 patients with progressive disease per RECIST, a considerable number of patients were reclassified to immune stable disease (six, 10.5%), immune partial response (two, 3.5%), and immune complete response (two, 3.5%) per iRECIST. Multivariable Cox regression models showed that both OR (hazard ratio [HR] 0.10, 95% confidence interval [CI] 0.03-0.35; P = 0.001) and TTP (HR 0.59, 95% CI 0.46-0.77; P

In the present guidelines for the management of metastatic castration-resistant prostate cancer (mCRPC), it is unclear who benefits most from androgen receptor axis-targeted agents (ARATs) or docetaxel as the first-line treatment. We conducted a retrospective study to explore new treatment-specific biomarkers in mCRPC. A total of 211 patients with mCRPC who received either ARAT or docetaxel as first-line treatment were included. Patients were compared for radiographic progression and prostate-specific antigen (PSA) progression. Multivariable Cox regression models were used to assess the association between pretreatment biomarkers and risk of events. The statistical interaction between biomarkers and clinical outcomes was also evaluated. Of all analyzed biomarkers, multivariable Cox regression models identified MPV [≤ median (9.7 fL)] as an independent prognostic factor of radiographic progression [hazard ratio (HR), 2.35; 95% confidence interval (CI), 1.15–4.80; P = 0.019] and PSA progression (HR, 1.96; 95% CI, 1.01–3.95; P = 0.048) in patients treated with ARAT, whereas such associations were not observed in those treated with docetaxel. Interaction analyses showed that those initially treated with docetaxel have lower risk of radiographic progression (HR, 0.33; 95% CI, 0.13–0.79; P = 0.014) and PSA progression (HR, 0.48; 95% CI, 0.23–0.98; P = 0.044) than ARAT when MPV was small. The present study identified pretreatment MPV as a significant treatment-specific prognostic factor of PSA and radiographic progression in patients with mCRPC who received first-line treatment. Furthermore, our results suggested that those with small MPV may better be treated initially with docetaxel than ARAT.

Background The purpose of this study was to investigate whether adding single immediate postoperative intravesical instillation of doxorubicin (SID) to transurethral resection of bladder tumor (TURBT) significantly reduced the risk of recurrence in patients with non–muscle-invasive bladder cancer (NMIBC). Materials and Methods We retrospectively analyzed the records of 720 patients diagnosed with primary NMIBC between 2002 through 2018 at the Kameda Medical Center. The primary outcome measure was time to recurrence. Time to progression was also compared. The cohort of SID and the cohort of TURBT alone were matched one-to-one by propensity scores. Matching was done by patient age, gender, and factors of the European Organization of Research and Treatment of Cancer recurrence risk table. The associations of adding SID and clinical outcomes were assessed with uni- and multivariate competing-risk regression models. Results After matching, a total of 364 patients, including 182 receiving SID and 182 receiving TURBT alone, were analyzed. No statistically significant differences existed among the measured baseline characteristics in propensity score-matched cohorts. In the multivariate analysis, there was a significantly longer time to recurrence in patients receiving SID (subdistribution hazard ratio, 0.68; 95% confidence interval, 0.49-0.95; P = .024) in propensity score-matched cohorts. There was no significant difference in time to progression (subdistribution hazard ratio, 0.61; 95% confidence interval, 0.11-3.49; P = .58) in univariate analysis. Conclusions Our results demonstrated that SID significantly reduced the recurrence risk of primary NMIBC. Doxorubicin could be an inexpensive alternative to other evidenced-based chemotherapeutic agents for single immediate intravesical chemotherapy.

To assess the prognostic value of sex for non-muscle-invasive/muscle-invasive bladder urothelial carcinoma (NMIBC/MIBC) treated with radical surgery.The PubMed, Web of Science, and Scopus databases were searched in November 2021 according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. Studies were deemed eligible if they involved the comparison of the overall, cancer-specific, progression, and recurrence-free survival of patients with NMIBC/MIBC. Formal sex-stratified meta-analyses of these outcomes were performed.Thirty-one studies, which included 32,525 patients with NMIBC, and 63 studies, which included 85,132 patients with MIBC, were eligible for review and meta-analysis. Female sex was associated with worse cancer-specific survival (pooled hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.11-1.31) and overall survival (pooled HR, 1.02; 95% CI, 1.00-1.05) in patients with MIBC. In contrast, however, sex was not associated with cancer-specific survival (pooled HR, 1.01; 95% CI, 0.70-1.46), progression-free survival (pooled HR, 1.04; 95% CI, 0.88-1.24), and recurrence-free survival (pooled HR, 1.06; 95% CI, 0.98-1.16) in patients with NMIBC.Sex is associated with an increased risk of worse survival outcomes in patients with MIBC but not in those with NMIBC. Given the genetic and social differences between sexes, sex may represent a key factor in the clinical decision-making process.

Serum C-reactive protein (CRP) is known to be a biomarker for systemic inflammatory reactions. In the present study, we sought to measure the predictive value of serum CRP level for metastatic renal cell carcinoma (mRCC) treated with first-line ipilimumab and nivolumab using our real-world clinical dataset including non-clear cell RCC (nccRCC). The clinical record of patients who underwent the first-line ipilimumab plus nivolumab treatment for mRCC including ccRCC and nccRCC from 2018 to 2021 was retrospectively analyzed. All patients were diagnosed with either intermediate or poor-risk group defined by IMCD (international metastatic RCC database consortium). In total, 74 patients were involved. The median age was 68 years and 24 (32.4%) patients deceased during the follow-up. Forty-five (61%) and 29 (39%) patients were classified into intermediate and poor-risk groups. The one-year overall survival (OS) rate and objective response rate were 65% and 41% for all 74 mRCC patients, respectively. The receiver operating characteristic curve identified 1.0 mg/dL of serum CRP level as an ideal cut-off for predicting overall survival (OS). Serum CRP > 1.0 mg/dL and nccRCC were the independent predictors for OS in 74 mRCC patients. OS for patients with CRP > 1 mg/dL was significantly shorter than those with CRP < 1 mg/dL in both ccRCC (58 patient: p = 0.009) and nccRCC (16 patients: p = 0.008). The present study indicated that serum CRP level is a prognostic indicator for OS in both ccRCC and nccRCC patients treated with the first-line ipilimumab plus nivolumab treatment.

BACKGROUND Pharmacobiological behavior differs between gonadotropin-releasing hormone (GnRH) antagonists and GnRH agonists. However, reliable evidence clarifying the difference between them is limited. OBJECTIVES We aimed to elucidate the difference in recovery profile between GnRH antagonist (degarelix) and GnRH agonist (leuprorelin acetate or goserelin acetate) as short-term (12 weeks) neoadjuvant androgen deprivation therapy (ADT) prior to 125I-transperineal prostate brachytherapy (TPPB) for localized prostate cancer. MATERIALS AND METHODS This study was initially designed as a single-center, prospective, open-label, randomized controlled trial. The primary endpoint was a serum testosterone level above the castration range (>50 ng/dl) after the cessation of 12-week neoadjuvant ADT (GnRH antagonist or GnRH agonists). All patients underwent 12 weeks of neoadjuvant ADT. The recovery profiles of hormones, prostate-specific antigen, total prostate volume (TPV), bone mineral density, and quality of life scores were investigated. RESULTS Testosterone recovery duration after the last injection was significantly longer in the GnRH antagonist arm than in the GnRH agonist arm (median, 27.3 vs. 4.8 weeks, p < 0.001). The serum levels of luteinizing hormone and follicle-stimulating hormone in the GnRH antagonist arm also remained significantly lower than those in the GnRH agonist arm between 16 and 24 weeks (p < 0.01). Meanwhile, reduction in TPV at the time of TPPB was comparable between both arms (p = 0.128). There were also no significant between-arm differences in the International Prostate Symptom Score and the International Index of Erectile Function scores. DISCUSSION AND CONCLUSION The recovery patterns of hormonal profiles after short-term (12 weeks) neoadjuvant ADT differ between GnRH antagonists and GnRH agonists. The choice between these drugs matters and may have a clinical impact depending on the primary objective of ADT.

Pembrolizumab has emerged as the new standard of care in patients with platinum-refractory metastatic urothelial carcinoma (mUC), whereas the optimal risk stratification to predict survival outcomes is still controversial. We examined a risk model for overall survival (OS) in mUC treated with pembrolizumab using our multi-institutional dataset (212 patients). The median age was 72 years old. Median OS from the initiation of pembrolizumab treatment was 11.7 months. The objective response rate (ORR) was 26.4%. On multivariate analysis, multiple metastatic sites and an NLR &gt, 3.50 at the initiation of pembrolizumab treatment were identified as independent predictors for OS. We next developed a risk model using those two predictors. Patients without any factors were assigned to the favorable-risk group (26.5%). Patients with either factor and both factors were assigned to the intermediate-risk group (44.3%), and poor-risk group (29.2%), respectively. Kaplan–Meier curves showed clear discrimination of OS among the risk groups (p &lt, 0.001). The ORR in each group was 35.7% in the favorable-risk group, 27.7% in the intermediate-risk group, and 17.7% in the poor-risk group. Given that the model can be concisely determined at the initiation of pembrolizumab treatment, physicians may be encouraged to consider the risk group for daily practice.

Among various therapeutic options available for metastatic castration-resistant prostate cancer (mCRPC), only apalutamide and enzalutamide have shown evidences of improved metastasis-free survival (MFS) for non-metastatic castration-resistant prostate cancer (nmCRPC). However, there is a paucity of evidence to indicate who may be targeted for aggressive therapy among patients with nmCRPC. The objectives of this retrospective study were to explore predictors of metastasis in patients with nmCRPC and to identify a subpopulation of patients with nmCRPC who may benefit from aggressive therapy. A total of 115 patients with CRPC who had no metastasis detected at the time of diagnosis of CRPC were included in this retrospective study. All patients were treated at Jikei University and its affiliated hospitals. The primary outcome measure was MFS from the time of diagnosis of CRPC. Predictors of MFS were also explored with a multivariate Cox hazard model. The median observation period after diagnosis of CRPC was 30 months (range 2–143 months). Kaplan–Meier analysis revealed a median MFS of 76. Multivariate analysis demonstrated that low alkaline phosphatase (ALP) values at diagnosis of CRPC and favorable response to primary androgen deprivation therapy (ADT) were significant predictors of longer MFS (P = 0.011, and 0.031, respectively). Results of this study suggest that high ALP values at diagnosis of CRPC and poor response to primary ADT may predict the propensity of metastasis in patients with nmCRPC. Further prospective studies will be required enrolling more patients to confirm our findings.

Type 2 diabetes—associated with impaired insulin/insulin-like growth factor-1 (IGF1) signaling (IIS)—is a risk factor for cognitive impairment and dementia including Alzheimer’s disease (AD). The insulin receptor substrate (IRS) proteins are major components of IIS, which transmit upstream signals via the insulin receptor and/or IGF1 receptor to multiple intracellular signaling pathways, including AKT/protein kinase B and extracellular-signal-regulated kinase cascades. Of the four IRS proteins in mammals, IRS1 and IRS2 play key roles in regulating growth and survival, metabolism, and aging. Meanwhile, the roles of IRS1 and IRS2 in the central nervous system with respect to cognitive abilities remain to be clarified. In contrast to IRS2 in peripheral tissues, inactivation of neural IRS2 exerts beneficial effects, resulting in the reduction of amyloid β accumulation and premature mortality in AD mouse models. On the other hand, the increased phosphorylation of IRS1 at several serine sites is observed in the brains from patients with AD and animal models of AD or cognitive impairment induced by type 2 diabetes. However, these serine sites are also activated in a mouse model of type 2 diabetes, in which the diabetes drug metformin improves memory impairment. Because IRS1 and IRS2 signaling pathways are regulated through complex mechanisms including positive and negative feedback loops, whether the elevated phosphorylation of IRS1 at specific serine sites found in AD brains is a primary response to cognitive dysfunction remains unknown. Here, we examine the associations between IRS1/IRS2-mediated signaling in the central nervous system and cognitive decline.

Most patients with metastatic urothelial carcinoma experience no objective response to pembrolizumab and have poor overall survival (OS). Here, we investigated the prognostic value of fluctuation in the neutrophil-lymphocyte ratio (NLR) at 6 weeks of pembrolizumab treatment, focusing on its association with the achievement of objective response.The clinical records of 177 metastatic urothelial carcinoma patients treated with pembrolizumab were retrospectively analyzed.The median age was 72 years, and the median OS was 14 months. The objective response rate in the total cohort was 26.5% (47 of 177 patients). Multivariable analysis showed that objective response achievement (hazard ratio 0.3 [95% confidence interval 0.15-0.59], P0.001) and decline in NLR from that at baseline at 6 weeks of treatment (0.54 [0.34-0.88], P = 0.013) were independent prognostic factors for improved OS. For 47 (26.5%) patients who achieved an objective response, OS was similar regardless of NLR fluctuation at 6 weeks of treatment (P = 0.723). Intriguingly, of the 130 (73.5%) patients with no objective response, those who showed a decreased NLR at 6 weeks of pembrolizumab treatment (57 patients) from that at baseline had significantly longer OS than those with elevated NLR (73 patients) (14 vs. 6 months, P = 0.007).The fluctuation in NLR from that at baseline at 6 weeks of pembrolizumab treatment may be useful for patients without an objective response. This could potentially aid decision-making for post pembrolizumab therapies.

The association of concurrent proton pump inhibitor (PPI) use with treatment outcome of metastatic urothelial carcinoma (UC) remains controversial.We retrospectively analyzed the records of 227 patients with platinum-treated metastatic UC treated with pembrolizumab. The primary outcome was overall survival (OS). Immune progression-free survival (iPFS) and objective response per immune response evaluation criteria in solid tumors were also compared. Inverse probability of treatment weighting (IPTW)-adjusted multivariable Cox regression models and an IPTW-adjusted multivariable logistic regression model were used to evaluate the oncological outcomes. Furthermore, the heterogeneity of the treatment effect on OS was examined using interaction terms within the IPTW-adjusted univariate Cox regression models.Overall, 86 patients (37.9%) used PPIs. After weighting, no significant differences in patient characteristics were observed between PPI users and non-users. PPI use was significantly associated with a shorter OS (hazard ratio [HR]: 2.02, 95% confidence interval [CI]: 1.28-3.18, P = 0.003) and iPFS (HR: 1.70, 95% CI: 1.23-2.35, P = 0.001). Although not statistically significant, PPI use was associated with objective response as well (OR: 0.61, 95% CI: 0.36-1.02, P = 0.06). The interaction analyses showed that the effect of PPI significantly decreased with age (HR: 0.97, 95% CI: 0.93-1.00, P[interaction] = 0.048) and was increased in males (HR: 2.97, 95% CI: 1.10-8.05, P[interaction] = 0.032).PPI use was significantly associated with worse survival of patients with metastatic UC treated with pembrolizumab. Furthermore, the results suggested that its effects decreased with age and was increased in males.

The primary advantage of en bloc resection of bladder tumors is to provide better diagnostic accuracy. However, the clinical significance of horizontal and vertical margin has not been demonstrated. We evaluated the clinical importance of surgical margins in patients who underwent en bloc resection of bladder tumors.We retrospectively analyzed the records of 140 consecutive patients who underwent en bloc resection of bladder tumors for nonmuscle invasive bladder cancer. We analyzed perioperative and oncological outcome, and compared patient demographics and recurrence-free survival for horizontal findings. The relationship between surgical margin and second transurethral resection outcome in pT1 bladder cancer was also analyzed.Mean tumor diameter was 17.2±9.8 mm. Pathological stages were 93 cases in pTa and 47 cases in pT1. Diagnostic rates for the horizontal and vertical margins were 63% and 99%, respectively. The rates of sessile, carcinoma in situ, high grade, and pT1 tumors were significantly higher in the horizontal margin positive group (41) than in the negative group (47). There was no significant difference in 2-year recurrence-free survival based on horizontal margin findings (negative: 72.4%, positive: 75.4%, p=0.87). A second transurethral resection was performed in 31 of the 47 pT1 patients; pT1 residue was seen only in vertical margin positive cases, and 5 pTa/pTis residues at the transurethral resection scar were seen in 15 horizontal margin positive patients.Horizontal margin positive findings were not associated with recurrence-free survival, but careful assessment is warranted regarding residue at the original site. A second transurethral resection should be considered in patients with horizontal and vertical margin positive pT1 bladder cancer.

The identification of early or primary resistance to androgen signaling inhibitors (ASIs) is of great value for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This study evaluates the predictive value of prostate-specific antigen (PSA) response at dour weeks of first-line ASIs treatment for mCRPC patients. A total of 254 patients treated with ASIs (abiraterone acetate: AA and enzalutamide: Enz) at the first-line treatment are retrospectively analyzed. Patients are stratified according to the achievement of &gt, 30% PSA decline at 4 and 12 weeks from the treatment initiation. At four weeks of the treatment, 157 patients (61.8%) achieved &gt, 30% PSA decline from the baseline. Thereafter, 177 patients (69.7%) achieved &gt, 30% PSA decline at 12 weeks of the treatment. A multivariate analysis exhibits &gt, 30% PSA decline at four weeks as an independent predictor for overall survival (OS). We note that 30 of 97 (30.9%) patients who did not achieve &gt, 30% PSA decline at four weeks consequently achieved &gt, 30% PSA decline at 12 weeks, and had a comparable favorable three years OS rate as the 147 patients achieving &gt, 30% PSA decline at both 4 and 12 weeks. To identify the variables that discriminate the patient survival in 97 patients without achieving &gt, 30% PSA decline at four weeks, a multivariate analysis is performed. The duration of androgen deprivation therapy before CRPC &le, 12 months and Eastern Cooperative Oncology Group Performance Status &ge, 1 are identified as independent predictors for shorter OS for those patients. These data offer a concept of early treatment switch after four weeks of first-line ASIs when not observing &gt, 30% PSA decline at four weeks&mdash, particularly in patients with a modest effect of ADT and poor performance status.

Purpose To investigate the prognostic role of the preoperative systemic immune–inflammation index (SII) in patients with upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU). Materials and methods We retrospectively analyzed our multi-institutional database to identify 2492 patients. SII was calculated as platelet count × neutrophil/lymphocyte count and evaluated at a cutoff of 485. Logistic regression analyses were performed to investigate the association of SII with muscle-invasive and non-organ-confined (NOC) disease. Cox regression analyses were performed to investigate the association of SII with recurrence-free, cancer-specific, and overall survival (RFS/CSS/OS). Results Overall, 986 (41.6%) patients had an SII > 485. On univariable logistic regression analyses, SII > 485 was associated with a higher risk of muscle-invasive (P = 0.004) and NOC (P = 0.03) disease at RNU. On multivariable logistic regression, SII remained independently associated with muscle-invasive disease (P = 0.01). On univariable Cox regression analyses, SII > 485 was associated with shorter RFS (P = 0.002), CSS (P = 0.002) and OS (P = 0.004). On multivariable Cox regression analyses SII remained independently associated with survival outcomes (all P P = 0.02). However, all area under the curve and C-indexes increased by Conclusions Preoperative altered SII is significantly associated with higher pathologic stages and worse survival outcomes in patients treated with RNU for UTUC. However, the SII appears to have relatively limited incremental additive value in clinical use. Further study of SII in prognosticating UTUC is warranted before routine use in clinical algorithms.

Objective To describe a novel technique allowing laparoscopic nephroureterectomy with bladder cuff excision and lymphadenectomy, in a complete supine position, without patient repositioning. Methods Between January 2016 and October 2018, 20 consecutive patients with upper urinary tract urothelial carcinoma underwent supine extraperitoneal laparoscopic nephroureterectomy. The patients were placed in the complete supine position. A 4-cm pararectal skin incision was made and the extraperitoneal space was developed. We used a unique port placement that permits complete access for nephroureterectomy, bladder cuff excision and concomitant lymphadenectomy. Operative parameters and pathological data were analyzed. Results The median age was 70 years (range 49-88 years), the mean operative time was 234 min (range 175-293 min) and the mean estimated blood loss was 67 mL (range 50-200 mL). There were no intraoperative complications, and no patients required transfusion or open conversion. The median number of removed lymph nodes was 10; only one patient had node metastasis. The total operative time and time for nephroureterectomy were significantly longer in the first 10 patients (first group) than in the second 10 patients (second group). Times required for bladder cuff excision and lymphadenectomy did not differ between the two groups. Conclusions Our novel technique, which enables completion of the entire procedure of nephrouretectomy with bladder cuff excision and lymphadenectomy in the supine position without patient repositioning, is safe and minimizes operative time while maintaining oncological efficacy. We believe this approach might become a standard option for patients with upper urinary tract urothelial carcinoma.

There has been no clinical evidence to justify continued pembrolizumab therapy beyond progression in patients with metastatic urothelial carcinoma (UC). We conducted a multicenter retrospective study evaluating the clinical efficacy of continued use of pembrolizumab beyond progression in patients with metastatic UC. Data from 51 patients with metastatic UC, who developed progression during second-line pembrolizumab therapy, were analyzed. Progression was defined based on the Immunotherapy Response Evaluation Criteria in Solid Tumors. The outcome was overall survival (OS). The association between continued treatment, OS, and the risk of all-cause mortality was tested using log-rank test, conventional and time-dependent Cox regression models. No significant difference in patient characteristics was noted between patients continuing pembrolizumab beyond progression (N = 21) and those discontinuing pembrolizumab (N = 30). Median OS was significantly longer in the continuation group (17.8 vs. 8.8 months; P = 0.038). A multivariable conventional Cox regression model identified continued pembrolizumab administration as a significant independent prognostic factor of all-cause mortality (hazard ratio [HR]: 0.21, 95% confidence interval [CI]: 0.05–0.90, P = 0.036), irrespective of the time from treatment initiation to progression and concurrent clinical progression. Further, longer duration of pembrolizumab treatment beyond progression was independently associated with a reduced risk of all-cause mortality in a multivariable time-dependent Cox regression model, when used as a time-dependent variable (HR: 0.07, 95% CI: 0.01–0.45, P = 0.006). Continued pembrolizumab administration beyond progression might be beneficial in patients with metastatic UC who were clinically stable.

To evaluate the clinical trifecta of percutaneous cryoablation (PCA) vs. laparoscopic partial nephrectomy (LPN) for cT1 renal tumors.We retrospectively analyzed the records of patients who had undergone 2 types of nephron sparing surgeries (NSS) PCA or LPN for cT1 renal tumors between November 2011 and December 2019. The cohorts were matched by one-to-one propensity scores based on patient demographics, renal function, and tumor complexity. Perioperative and oncological outcomes and preservation of renal function following surgery were compared.After matching, a total of 180 patients who had undergone NSS for de novo renal tumors were evaluable: 90 for PCA and 90 for LPN. No statistically significant differences were noted among the measured baseline characteristics in the propensity score-matched cohorts. Overall perioperative complication rates were 5.5% in the PCA and 11.1% in the LPN groups (P = 0.28). The rate of eGFR preservation 1 to 3 months after surgery was significantly higher for PCA than for LPN (92.8 ± 11.5% vs. 88.5 ± 14.6%, P = 0.03). Median follow-up was 33 months for PCA and 18 months for LPN (P0.001). Three residual and 4 recurrent tumors were later diagnosed in the PCA group and 1 recurrent tumor in the LPN group. The 5-year local recurrence-free survival was lower for PCA than LPN (90.2% vs. 98.5%, P = 0.36). The 5-year metastasis-free survival rate was similar in both groups (98.4% vs. 100%, P = 0.38). The 5-year overall and cancer-specific survival rates were comparable in both groups (91.7% vs. 98.9%, P = 0.53, and 95% vs. 100%, P = 0.55, respectively).Clinical T1 RCC patients are better treated with LPN if technically possible. Though PCA had a higher local recurrence rate, medium-term local control was not inferior to LPN. Additionally, PCA patients tended to retain renal function without severe complications. PCA appears to be a reasonable option for patients with high comorbidity at presentation.

BackgroundChemoradiation therapy (CRT) has been increasingly reported as a possible alternative to total cystectomy (TC) for localized bladder cancer (BC). Pembrolizumab is the standard of care for platinum-refractory metastatic urothelial carcinoma, although it is unknown whether the efficacy of pembrolizumab in patients previously treated with curative CRT varies from the results of benchmark trials.MethodsWe retrospectively assessed whether the survival benefit of pembrolizumab differs between patients previously treated with TC or CRT as radical treatment. A total of 212 patient records were collected for a logistic regression propensity score model. An independent dataset with next-generation sequencing (n=289) and PD-L1 Combined Positive Score (CPS: n=266) was analyzed to assess whether CRT-recurrent tumor harbors distinct CD274/PD-L1 profiles.ResultsPropensity score matching was performed using putative clinical factors, from which 30 patients in each arm were identified as pair-matched groups. There was no significant difference in overall survival from the initiation of pembrolizumab (p=0.80) and objective response rate (p=0.59) between CRT and TC treatment groups. In the independent 289 BC cohort, 22 samples (7.6%) were collected as CRT-recurrent tumors. There was no significant difference in CD274 mRNA expression level between CRT-naïve and CRT-recurrent tumors. The compositions of CD274 isoforms were comparable among all isoforms detected from RNAseq between CRT-naïve (n=267) and CRT-recurrent (n=22) tumors. No actionable exonic mutation in CD274 was detected in CRT-recurrent tumors. PD-L1 CPS was positively correlated with CD274 mRNA expression level, and PD-L1 CPS was comparable between CRT-naïve and CRT-recurrent tumors.ConclusionsThe efficacy of pembrolizumab for patients previously treated with CRT was similar to those treated with TC. The enhanced tumor regression by combining programmed cell death protein 1/PD-L1 inhibitor and CRT might be expected only in the concurrent administration.

Introduction Surgical manipulation of a pheochromocytoma carries the risk of releasing catecholamines into bloodstream leading to severe intraoperative hypertension. Case presentation We present three patients with right adrenal pheochromocytoma over 10 cm diameter: a 40-year-old woman, 63-year-old man, and 66-year-old woman. They were diagnosed by 123I-MIBG scintigraphy and received preoperative antihypertensive treatment with 16 mg/day of doxazosin. Open adrenalectomy was performed with early right adrenal artery ligation between the inferior vena cava and ventral aorta (Step 1) as well as between the tumor and upper pole of the right kidney (Step 2). There was no severe intraoperative hypertension, and no recurrence was observed over 33 months, postoperatively. Conclusion Early adrenal artery ligation may stop tumor blood supply and significantly reduce the catecholamine release. Our technique was thought to be safe and useful for preventing severe intraoperative hypertension in giant right adrenal pheochromocytoma.

Age‐related reduction in adult hippocampal neurogenesis is correlated with cognitive impairment. Diabetes is a chronic systemic disease that negatively affects adult neural stem cells and memory functions in the hippocampus. Despite growing concern regarding the potential role of diabetic drugs in neural abnormalities, their effects on progressive deterioration of neurogenesis and cognitive functions remain unknown. Here, we show that the combination of aging and diabetes in mice causes a marked decrease in hippocampal neurogenesis along with memory impairment and elevated neuroinflammation. Prolonged treatment with metformin, a biguanide antidiabetic medication, promotes cell proliferation and neuronal differentiation and inhibits aging‐ and diabetes‐associated microglial activation, which is related to homeostatic neurogenesis, leading to enhanced hippocampal neurogenesis in middle‐aged diabetic mice. Although chronic therapy with metformin fails to achieve recovery from hyperglycemia, a key feature of diabetes in middle‐aged diabetic mice, it improves hippocampal‐dependent spatial memory functions accompanied by increased phosphorylation of adenosine monophosphate‐activated protein kinase (AMPK), atypical protein kinase C ζ (aPKC ζ), and insulin receptor substrate 1 (IRS1) at selective serine residues in the hippocampus. Our findings suggest that signaling networks acting through long‐term metformin‐stimulated phosphorylation of AMPK, aPKC ζ/λ, and IRS1 serine sites contribute to neuroprotective effects on hippocampal neurogenesis and cognitive function independent of a hypoglycemic effect.